Delivery of genes to target cells by receptor-mediated endocytosis is a very appealing strategy for gene therapy. Many of the targets for gene therapy are epithelial cells that line a variety of important organs. For instance, airway cells are the main site of expression of the cystic fibrosis transmembrane conductance regulator (CFTR), which is the lesion in cystic fibrosis. Epithelial cells have an apical surface facing the lumen, and a basolateral surface facing underlying cells. Ideally, one would like to deliver genes through the apical or luminal surface of epithelial cells. In the lung, for instance, one could deliver the genes by introduction into the airways, via instillation or even aerosolization. However, the apical surface of most epithelial cells presents a formidable barrier to gene delivery. Most delivery methods, such as liposomes or viral vectors, work very poorly when applied to the apical surface of well polarized epithelial cells in culture or especially in vivo. The receptors that are usually used for receptor-mediated gene delivery are all located at the basolateral surface. The apical surface contains few receptors that are efficiently endocytosed. One receptor that has been used for basolateral gene delivery is the polymeric immunoglobulin receptor (pIgR), which is particularly abundant on the airway cells that express CFTR. Ordinarily, the extracellular domain of pIgR is cleaved off at the apical surface, which makes this receptor difficult to use for apical gene uptake. We have found a novel method to use the pIgR for effective apical gene uptake. In this pilot grant proposal we will test this in cultured airway epithelial cells and in the lungs of whole rats.